Effects of yeast cell wall-derived mannan-oligosaccharides on jejunal gene expression in young broiler chickens.

The use of mannan-oligosaccharides (MOS) as alternatives to antibiotic growth promoters (AGP) has gained in popularity in recent years due to regulatory restrictions of using AGP in food animal production. Benefits of MOS usage include improvement on animal performance, feed efficiency, and gastrointestinal health. The molecular mechanisms of these functions however are not clear. The goal of the current study was to use a transcriptomics approach to investigate the effects of MOS on the intestinal gene expression profile of young broilers and characterize biological gene pathways responsible for the actions of MOS. One hundred and twenty 1-d-old Cobb 500 broiler chicks were randomly divided into 2 groups and were fed either a standard wheat-soybean meal-based (control) diet or the same diet supplemented with 2.2 g/kg of MOS (Bio-Mos, Alltech, Nicholasville, KY) for 3 wk, followed by jejunal gene expression profiling analysis using chicken-specific Affymetrix microarrays. Results indicated that a total of 672 genes were differentially expressed (P < 0.01 and fold change >1.2) in the jejunum by MOS supplementation. Association analysis indicated that differentially expressed genes are involved in diverse biological functions including energy production, cell death, and protein translation. Expression of 77 protein synthesis-related genes was differentially regulated by MOS in the jejunum. Further pathway analysis indicated that 15 genes related to oxidative phosphorylation were upregulated in the jejunum, and expression of genes important in cellular stress response, such as peroxiredoxin 1, superoxide dismutase 1, and thioredoxin, were also increased by MOS. Differential expression of genes associated with cellular immune processes, including lysozyme, lumican, ß 2-microglobin, apolipoprotein A-1, and fibronectin 1, were also observed in MOS-fed broilers. In summary, this study systematically identified biological functions and gene pathways that are important in mediating the biological effects of MOS in broilers.

Treatment of advanced hepatocellular carcinoma with very low levels of amplitude-modulated electromagnetic fields.

BACKGROUND: Therapeutic options for patients with advanced hepatocellular carcinoma (HCC) are limited. There is emerging evidence that the growth of cancer cells may be altered by very low levels of electromagnetic fields modulated at specific frequencies. METHODS: A single-group, open-label, phase I/II study was performed to assess the safety and effectiveness of the intrabuccal administration of very low levels of electromagnetic fields amplitude modulated at HCC-specific frequencies in 41 patients with advanced HCC and limited therapeutic options. Three-daily 60-min outpatient treatments were administered until disease progression or death. Imaging studies were performed every 8 weeks. The primary efficacy end point was progression-free survival 6 months. Secondary efficacy end points were progression-free survival and overall survival. RESULTS: Treatment was well tolerated and there were no NCI grade 2, 3 or 4 toxicities. In all, 14 patients (34.1%) had stable disease for more than 6 months. Median progression-free survival was 4.4 months (95% CI 2.1-5.3) and median overall survival was 6.7 months (95% CI 3.0-10.2). There were three partial and one near complete responses. CONCLUSION: Treatment with intrabuccally administered amplitude-modulated electromagnetic fields is safe, well tolerated, and shows evidence of antitumour effects in patients with advanced HCC.

Effects of feeding different concentration and forms of zinc on the performance and tissue mineral status of broiler chicks.

1. Two studies were conducted to investigate the effect of feeding different concentration and forms of zinc (Zn) on the performance and tibia Zn status of broiler chicks. 2. In Experiment 1, chicks fed on the control or the diet supplemented with 12?mg of Zn as sulphate had lower feed intake, weight gain and tibia Zn content than other treatment groups. Chicks given 12 and 24 mg of organic Zn in starter and grower phases, respectively, had the same performance and tibia Zn content as those fed 40 mg of Zn as sulphate and the same performance but higher tibia Zn content than those given 12 mg of Zn as organic over the 42 d. 3. In Experiment 2, chicks given 24 mg organic Zn had greater weight gain than chicks fed on the other treatment diets in the starter period. Chicks fed on the control diet had lower tibia Zn content than chicks fed other treatment diets. Chicks given 80 mg Zn as sulphate had higher tibia Zn content than chicks fed the other treatment diets except those given 40 mg of Zn as sulphate. 4. The results from these trials indicate that feeding lower concentration of Zn as organic form may better promote the growth performance of broiler chicks.

Effects of feeding different forms of zinc and copper on the performance and tissue mineral content of chicks.

A study was conducted to investigate the effects of feeding inorganic or organic Zn and Cu on the performance and tissue mineral content of chicks. A corn-soybean meal diet without Cu and Zn supplementation, containing 31 mg of Zn/kg of diet and 6.6 mg of Cu/kg of diet, was used as a basal diet. Organic Zn (a chelated Zn proteinate) and organic Cu (a chelated Cu proteinate) were used as organic sources for comparison with inorganic reagent-grade sulfates. Supplements provided 20 mg/kg of Zn and 8 mg/kg of Cu. A 3x3 factorial arrangement of treatments consisting of feeding the basal diet with 3 supplements (none, sulfate, or organic) of Cu and of Zn was used. Ten groups of 6 one-day-old male broilers were assigned to each of 9 dietary treatments. Tap water and feed were supplied on an ad libitum basis during the 3-wk trial. The Zn and Cu content in the mucosa of the duodenum of the chick was determined. Dietary supplementation of Zn increased (P<0.01) weight gain, feed intake, and G:F of chicks. The G:F for chicks fed both inorganic sources of Zn and Cu was lower (P<0.01) than that for chicks fed only the inorganic source of Zn. Dietary inclusion of Zn increased (P<0.01) tibia and plasma Zn content. The tibia Zn content for chicks fed organic Zn was higher (P<0.01) than that for chicks fed inorganic Zn. Liver Cu content was decreased (P<0.05) by dietary inclusion of Zn. The Zn and Cu contents in the mucosa of chicks fed the organic source were higher (P<0.01) than those of chicks fed the control diet. The feed conversion data suggest that the antagonism between Zn and Cu occurred when the inorganic forms, but not organic forms, of these 2 minerals were included in a chick diet.

Effect of enzyme supplementation and acidification of diets on nutrient digestibility and growth performance of broiler chicks.

Two experiments were conducted to examine the effects of alpha-galactosidase supplementation and acidification of diets on nutrient digestibility and growth performance of broiler chicks. In experiment 1, dietary treatments consisted of feeding a low-energy basal diet (2.74 Mcal of ME/kg) alone, the basal diet supplemented with 1,724 units of alpha-galactosidase per kg, the basal diet supplemented with 2% citric acid, or the basal diet supplemented with both. alpha-Galactosidase significantly increased feed intake, weight gain, AME(n) of the diets, and retention of CP and neutral detergent fiber (NDF) (P < 0.05). Citric acid significantly increased the retention of DM, CP, and NDF, but decreased feed intake and weight gain. The greatest values for DM and NDF retention and for AME(n) were obtained with the combination of alpha-galactosidase plus citric acid. In experiment 2, chicks were fed diets with 2 levels of energy (2.74 or 3.11 Mcal/kg), 2 levels of citric acid (0 or 1.5%), and 2 levels of alpha-galactosidase (0 or 1,724 units/kg) in a 2 x 2 x 2 factorial arrangement of treatments. alpha-Galactosidase significantly increased the reducing sugar concentration in the crop content, whereas citric acid decreased the pH and increased the reducing sugar concentration in the crop content. Citric acid decreased the gain to feed ratio in the absence but not in the presence of alpha-galactosidase. The data from these studies indicate that acidification of diet improves the efficacy of alpha-galactosidase.

Effect of manganese preconditioning and replacing inorganic manganese with organic manganese on performance of male broiler chicks.

The effects of manganese (Mn) preconditioning, 96 h post-hatch followed by the replacement of inorganic Mn with different levels of organic Mn (5 to 21 D), on growth, tissue excreta Mn content, gene expression, and enzyme activity were evaluated. A total of 420 day-old male Cobb 500 broilers were divided into 2 groups. One group was fed a corn-soybean meal basal diet containing 17 mg of Mn/kg (preconditioning diet, MnPD); the second group was fed the non-preconditioning diet (NPCD), which was the MnPD supplemented with 60 mg of Mn/kg from manganese sulfate (MnSO4). On day 5, each group was divided into 5 subgroups and were randomly assigned to dietary treatments consisting of MnPD alone or MnPD supplemented with 12 or 60 mg Mn/kg Mn as MnSO4 or Mn proteinate (6 replicate cages of 6 birds). Broiler chicks that were fed the MnPD had lower (P ≤ 0.05) body weight gain (BWG) and G:F ratio when compared to those that were fed the NPCD for 4 D. Birds that were fed MnPD (1 to 4 D) and switched to MnPD supplemented with 60 mg/kg Mn (5 to 21 D) had lower (P ≤ 0.05) BWG compared to those that were fed NPCD (1 to 4 D) and switched to MnPD supplemented with 60 mg/kg Mn for 21 D. Excreta, tibia ash, liver, and heart Mn levels were increased (P ≤ 0.05) by supplemental Mn. The expression of jejunum divalent metal transporter-1 mRNA levels, as well as activities of plasma total super oxide dismutase and liver alanine transaminase, was not affected by MnPD or Mn source and levels. These results confirmed that feeding marginally deficient Mn diets to broiler chicks post-hatch does affect growth rate and tissue Mn concentration.

Hematopoietic development: a balancing act.

Over the past year, significant new insights have been gained in our understanding of the lineage determination of red blood cells. In particular, evidence has emerged demonstrating that cross-antagonism of lineage-specific transcription factors plays an important role in determining cell phenotype by actively repressing alternate lineage gene programs.

A global genome damage score predictive of lung cancer patients outcome.

Genome damage is a hallmark of human cancer. Efforts at assessing the impact of genome damage on tumor phenotype and patients outcome have focused on measurements of the relative DNA content in tumor cells compared to normal cells and the assessment of allelic loss at single or multiple selected loci that are thought to harbor genes important in cancer biology. We adapted a global, high-resolution genotyping method for determination of global and unbiased allelic loss. We generated a score, termed global genome damage score (GGDS), that is a continuous variable from zero to one and a measure of the extent of damaged DNA in individual tumors. In 71 patients with completely resected non-small-cell lung cancer, the GGDS ranged from 0.0006 to 0.5530 with a median value of 0.0401 indicating that between 0.06 and 55.3% of the genome has allelic loss. Patients with high scores (>0.04) had a significantly worse outcome than those with low scores (median overall survival time 35.5 vs >120.0 months, P=0.006 log-rank test; median disease-free survival 28.3 vs >120.0 months, P=0.003 log-rank test). This suggests that the clinical behavior of lung tumors with low GGDS is relatively benign whereas tumors with high GGDS are aggressive resulting in early death of patients.

Effects of organic zinc and phytase supplementation in a maize-soybean meal diet on the performance and tissue zinc content of broiler chicks.

1. The purpose of this study was to investigate the effects of Bioplex Zn (a chelated zinc proteinate) and phytase supplementation in a maize-soybean meal diet on the performance and tissue zinc (Zn) content of broiler chicks. Treatment structure consisted of a 2 x 6 factorial arrangement with two inclusions of phytase (0 or 500 PU/kg) and 6 of Bioplex Zn providing 0, 2, 4, 8, 16 and 32 mg Zn/kg diet. A total of 864 chicks were randomly assigned to each of 12 dietary treatments with 6 replicate cages of 12 chicks. 2. Dietary inclusion of phytase increased feed intake, weight gain, plasma Zn content, tibia Zn content, tibia and ash weight. 3. Dietary supplementation of Bioplex Zn linearly increased feed intake, weight gain, gain to feed ratio, plasma Zn concentration, liver Zn concentration, tibia Zn content, tibia and ash weight. 4. An interactive effect of phytase and Bioplex Zn on feed intake, weight gain, tibia Zn concentration and tibia ash weight was found. 5. One slope, straight broken-line analysis of weight gain regressed on the supplemental Zn level provided as Bioplex Zn indicated that 12 mg/kg supplemental Zn without phytase and 7.4 mg/kg supplemental Zn with phytase were required for the optimal weight gain of chicks.

Effect of zinc imprinting and replacing inorganic zinc with organic zinc on early performance of broiler chicks.

The goal of this study was to determine the effects of feeding a zinc (Zn) deficient diet to broiler chicks for 96 h post-hatch followed by feeding diets with different Zn sources and supplemental levels (5 to 21 d) on the growth performance, tissue, and excreta Zn content. At the start of the study, four hundred 20-day-old male broiler chicks were divided into two groups. One group was fed a corn soybean meal based diet containing 25 mg of Zn/kg (imprinting diet, ID). The second group was fed the basal diet supplemented with 40 mg of Zn/kg from Zn oxide (ZnO) (non-imprinting diet, NID). Both groups were fed these diets for 96 h. At d 5, chicks from each group were randomly assigned to the dietary treatments consisting of the basal diet alone or the basal diet supplemented with 8 or 40 mg/kg Zn as ZnO or Zn proteinate. Main effects of post-hatch Zn ID were observed on feed intake and G:F. ID decreased (P < 0.05) feed intake and improved (P < 0.05) the gain to feed ratio (G:F) of 14 and 21 d old chicks compared to G:F of chicks fed NID. Additionally, G:F for 14 and 21 d was improved (P < 0.05) by interaction of Zn source × level. Furthermore, at d 21 chicks fed the ID had a lower (P < 0.05) Zn content in the tibia ash and excreta, and a higher (P < 0.05) Zn content in the pancreas tissue compared to chicks fed NID. These results suggest that Zn imprinting can affect body Zn stores and early performance.

Contextual factors influencing the implementation of the obstetrics hemorrhage initiative in Florida.

OBJECTIVE: The purpose of this study was to explore the multilevel contextual factors that influenced the implementation of the Obstetric Hemorrhage Initiative (OHI) among hospitals in Florida. STUDY DESIGN: A qualitative evaluation was conducted via in-depth interviews with multidisciplinary hospital staff (n=50) across 12 hospitals. Interviews were guided by the Consolidated Framework for Implementation Research and analyzed in Atlas.ti using rigorous qualitative analysis procedures. RESULT: Factors influencing OHI implementation were present across process (leadership engagement; engaging people; planning; reflecting), inner setting (for example, knowledge/beliefs; resources; communication; culture) and outer setting (for example, cosmopolitanism) levels. Moreover, factors interacted across levels and were not mutually exclusive. Leadership and staff buy-in emerged as important components influencing OHI implementation across disciplines. CONCLUSION: Key contextual factors found to influence OHI implementation experiences can be useful in informing future quality improvement interventions given the institutional and provider-level behavioral changes needed to account for evolving the best practices in perinatology.

Genetic staging of unresectable or metastatic neuroblastoma in infants: a Pediatric Oncology Group study.

BACKGROUND: Current staging systems for unresectable or metastatic neuroblastoma do not reliably predict responses to chemotherapy in infants under 1 year of age. Previous studies have indicated that the DNA content, or ploidy, of malignant neuroblasts can discriminate between good and poor responders in this group of patients, but the clinical utility of ploidy assessment has remained in question. PURPOSE: We tested, in a prospective nonrandomized study, the hypothesis that neuroblast ploidy could be used as the sole guide for treatment selection in infants with unresectable or metastatic tumors and could differentiate between those who would respond to our previous standard regimen and those who would benefit from an immediate switch to another therapy. METHODS: One hundred seventy-seven infants were enrolled in this trial. Five of these infants were subsequently excluded (two ineligible, two lacking ploidy information, and one protocol violation); therefore, 172 patients were included in the study. One hundred thirty infants with hyperdiploid tumors (DNA index > 1.0; better prognosis in retrospective studies) were treated with a well-tolerated regimen of cyclophosphamide (150 mg/m2 per day orally or intravenously on days 1-7) and doxorubicin (35 mg/m2 intravenously on day 8). Forty-two infants with diploid tumors (DNA index = 1.0; worse prognosis in retrospective studies) received cisplatin (90 mg/m2 intravenously on day 1) and teniposide (100 mg/ m2 intravenously on day 3) after an initial course of cyclophosphamide plus doxorubicin. Statistical end points were response and long-term survival. In addition, we assessed within each ploidy group (i.e., patients with hyperdiploid tumors and those with diploid tumors) the prognostic significance of NMYC gene copy number, tumor stage, and other variables commonly measured in this disease. RESULTS: Of the 127 assessable infants with hyperdiploid tumors, 115 (91%) had complete responses--85 after receiving five courses of cyclophosphamide plus doxorubicin and 30 after receiving further therapy including cisplatin plus teniposide. The 3-year survival estimate for the entire hyperdiploid group was 94% (95% confidence interval [CI] = 89%-98%). Nineteen (46%) of 41 assessable infants with diploid tumors were complete responders. The overall 3-year survival estimate for this group was 55% (95% CI = 39%-70%). Prognostic factor analysis indicated that NMYC gene amplification and an elevated serum lactate dehydrogenase level were statistically significant markers of higher risk disease within the diploid group (two-sided P values of .005 and .003, respectively). Only NMYC was predictive in the hyperdiploid group (P = .003). CONCLUSION: Use of a prognostic staging system based on tumor cell ploidy, augmented with the NMYC gene copy number and serum level of lactate dehydrogenase, would very likely improve the treatment of infants with unresectable or metastatic neuroblastoma. Patients with diploid tumors characterized by an amplified NMYC locus represent a particularly unfavorable risk group that may benefit from innovative new therapies.

Loss of heterozygosity for chromosomes 1 or 14 defines subsets of advanced neuroblastomas.

Neuroblastomas have been characterized genetically by N-myc amplification and by deletions or loss of heterozygosity (LOH) for the short arm of chromosome 1. However, recent studies have suggested deletion or allelic loss involving at least three other chromosome arms, 11q, 14q, and 17p. Therefore, we undertook an analysis of allelic loss for these respective chromosomal arms to determine the frequency and pattern of LOH as well as the correlation of these findings with other biological and clinical variables. A group of 24 pairs of normal and tumor DNAs was chosen that were representative of patients of different ages and stages. A substantial frequency of LOH (greater than or equal to 20%) was found only for 1p and 14q, whereas LOH for the other chromosome arms occurred in less than or equal to 5% of cases. On the basis of these results, we extended the analysis to a total of 59 neuroblastomas, and we found 1p LOH in 15 of the 59 cases (25%) and 14q LOH in 10 of 43 informative cases (23%). N-myc amplification was found in 15 of the 59 cases (25%). This analysis confirmed that 1p LOH and 14q LOH occurred almost exclusively in patients with advanced stages of disease. Furthermore, LOH for 1p and 14q usually occurred independent of each other, and 1p LOH frequently was associated with N-myc amplification, whereas 14q LOH was not. Thus, our results demonstrate that neuroblastomas are complex genetically and that there are at least two distinct loci for putative suppressor genes that are deleted independently in this tumor, both of which are associated with advanced stages of disease.

Loss of p21WAF1/CIP1 accelerates Ras oncogenesis in a transgenic/knockout mammary cancer model.

Upregulation of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 and subsequent cell growth arrest or senescence is one mechanism by which normal cells are believed to respond to stress induced by the constitutively activated GTPase Ras. We hypothesize that in the absence of p21, the onset of Ras-dependent oncogenesis is accelerated. To test this hypothesis, we crossed MMTV/v-Ha-ras transgenic mice into a p21-deficient background. By 63 days of age, all 8 ras/p21-/- mice developed either malignant (mammary and/or salivary adenocarcinomas) or benign (Harderian hyperplasia) tumors. In contrast, by the same age, only one out of nine of the ras/p21+/+ mice developed a tumor. Furthermore, by 94 days of age, half of the ras/p21-/- mice, but none of the ras/p21+/+ mice, developed mammary tumors. p21-deficiency also accelerated the development of salivary (T50=66 days for ras/p21-/- vs T50=136 days for ras/p21+/+) and Harderian (T50=52 days for ras/p21-/- vs T50>221 days for ras/p21+/+) tumors. Furthermore, two out of the eight ras/p21-/- mice had metastatic lesions, one in its lungs, the other in its abdomen. None of the nine ras/p21+/+ mice had metastatic lesions. By 4 months of age, the mammary tumor multiplicity was 10-fold greater in ras/p21-/- (average 3.40 tumors/mouse) than in ras/p21+/+ (average 0.33 tumor/mouse) mice. However, once the tumors appeared, their growth rate, apoptosis level, and mitotic index were not affected by the loss of p21, suggesting that loss of p21 is critical in early but not late events of Ras oncogenesis. Altogether, the results show that tumor onset in MMTV/v-Ha-ras mice is p21-dependent with loss of p21 associated with earlier tumor appearance and increased tumor multiplicity and aggressiveness.

Cisplatin, vincristine, and fluorouracil therapy for hepatoblastoma: a Pediatric Oncology Group study.

PURPOSE: To estimate the disease-free survival rate in children with grossly resected hepatoblastoma treated with cisplatin, vincristine, and fluorouracil (CDDP/VCR/FU) and to assess the disease-response rate and disease-free survival (DFS) rate in children with unresectable or metastatic tumors treated with this combination. PATIENTS AND METHODS: Sixty assessable patients with hepatoblastoma received therapy with five (stage I and II) to seven (stage III and IV) courses of CDDP (90 mg/m2), day 1, and VCR (1.5 mg/m2), and FU (600 mg/m2), day 3. RESULTS: Nineteen of 21 patients with stage I or II disease survive free of disease (actuarial survival, 90% at 5 years). Twenty-four of 31 patients with stage III disease achieved a complete remission (CR) after chemotherapy and surgical excision; actuarial DFS at 4 years is 67%. Only one of eight patients with stage IV disease achieved a remission and survives. CONCLUSION: Relatively brief exposure to chemotherapy with CDDP/VCR/FU provided excellent disease control to patients with grossly resected tumors. In patients with initially unresectable disease, this therapy provides a response rate and DFS rate comparable to regimens that contain doxorubicin (DOX).

Intensive chemotherapy and low-dose radiotherapy for the treatment of advanced-stage Hodgkin's disease in pediatric patients: a Pediatric Oncology Group study.

Sixty-two patients with advanced-stage Hodgkin's disease and a median age of 12 years (range, 3 to 22 years) were treated with four cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) alternating with four cycles of doxorubicin, vinblastine, bleomycin, and dacarbazine (ABVD) followed by low-dose radiotherapy (RT). We determined the feasibility, immediate safety, and rapidity of response of patients to this regimen, as well as the relationship between prognostic factors and the rate of complete remission (CR), event-free survival (EFS), and overall survival. Therapy was well tolerated, and the major toxicity was hematopoietic. At the end of chemotherapy, 54 of 62 patients (87%) were in CR by clinical restaging, with a biopsy of residual disease where necessary. The actuarial 3-year EFS is 77% (SE, 11%), with a median follow-up of 35 months, and the survival is 91% (SE, 7%). With respect to EFS, female patients and those with stage II or III disease fared statistically better than males and patients with stage IV disease, respectively. Six patients have died: three of progressive Hodgkin's disease, one of secondary acute myelocytic leukemia (AML), one of secondary non-Hodgkin's lymphoma (NHL), and one of overwhelming bacterial sepsis. The Pediatric Oncology Group (POG) is currently engaged in a randomized study of these eight cycles of chemotherapy with and without RT to assess the role of RT in achieving comparable results.

The prognostic significance of autologous bone marrow transplant in advanced neuroblastoma.

This report provides strong evidence for conducting a controlled randomized clinical trial of autologous bone marrow transplantation versus conventional chemotherapy in childhood neuroblastoma, which is disseminated beyond the intracavity nodes, and which is diagnosed in children older than 12 months of age. On the basis of two Pediatric Oncology Group (POG) studies, one a surgery plus conventional chemotherapy study (POG 8441) and the other an elective autologous transplant pilot protocol (POG 8340), there was no significant prognostic benefit of switching in remission from the surgery plus chemotherapy protocol to the transplant protocol (P = .91) or of switching in remission from the surgery plus chemotherapy protocol to any transplant (P = .75). The analysis is based on 116 patients achieving a complete or partial remission, 32 of whom received transplants on the pilot protocol, and 17 of whom received transplants outside the pilot protocol. While potential selection bias precludes cause-effect conclusions, these data strongly suggest that a large randomized trial of autologous bone marrow transplantation should be conducted before accepting this form of therapy as standard.

With modern imaging techniques, is staging laparotomy necessary in pediatric Hodgkin's disease? A Pediatric Oncology Group study.

PURPOSE: To determine whether the information gained from staging laparotomy can be predicted by imaging and/or clinical factors in children with Hodgkin's disease. PATIENTS AND METHODS: Between 1986 and 1991, 216 consecutive pediatric patients with Hodgkin's disease underwent laparotomy and were treated on two concurrent protocols in a multiinstitutional cooperative group. All patients had computed tomography (CT) of the chest, abdomen, and pelvis. Clinical factors studied included sedimentation rate, B symptoms, histology, number and location of involved sites, sex, mediastinal involvement, and age. Pretreatment CTs were centrally reviewed in 88 cases for the presence and size of both supradiaphragmatic and infradiaphragmatic lymph nodes, intrinsic spleen lesions, and splenic size. Models were generated that were predictive of any abdominal disease, splenic involvement, extensive splenic involvement, and upstaging at the laparotomy. False-positive and false-negative rates were calculated. RESULTS: For the end point of any abdominal disease, a model based on B symptoms, histology, sedimentation rate, and number and location of involved sites was highly significant (P < .0001). However, the success in predicting abdominal disease in an individual patient was limited: false-negative rate, 26%; false-positive rate, 32%. Highly significant models based on clinical factors and/or radiographic findings were also generated to predict splenic involvement, extensive splenic involvement, and upstaging with laparotomy, but they also had high false-positive and false-negative rates. CONCLUSION: Laparotomy findings cannot be predicted accurately in the majority of patients based on knowledge of CT findings and clinical factors.

Randomized study of intensive MOPP-ABVD with or without low-dose total-nodal radiation therapy in the treatment of stages IIB, IIIA2, IIIB, and IV Hodgkin's disease in pediatric patients: a Pediatric Oncology Group study.

PURPOSE: To determine whether the addition of low-dose total-nodal irradiation (TNI) in pediatric patients with advanced-stage Hodgkin's disease who have received eight cycles of alternating mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) will improve the event-free survival (EFS) and overall survival (OS) when compared with patients who have received chemotherapy only. PATIENTS AND METHODS: At diagnosis, 183 children and adolescents with stages IIB, IIIA2, IIIB, and IV Hodgkin's disease were randomized to receive eight cycles of alternating MOPP-ABVD with or without low-dose TNI. RESULTS: Of 183 patients, four were rendered ineligible before treatment was initiated. One hundred sixty-one of 179 patients (90%) were in complete remission (CR) at the completion of eight cycles of alternating MOPP-ABVD; 81 were in the chemotherapy-only group and proceeded to observation off therapy, whereas 80 of 161 were to receive combined modality therapy (CMT). Nine of 80 patients randomized at the time of diagnosis to receive CMT did not receive radiation (RT) because of a protocol violation, but were monitored for EFS and OS and included in all analyses. The estimated EFS and OS rates at 5 years for the 179 eligible patients are 79% and 92%, respectively. The actuarial EFS at 5 years was 80% for patients who received CMT and 79% for patients who received MOPP-ABVD only. The OS for the former group is estimated to be 87% and for the latter patients 96%. Age < or = 13 years of age at diagnosis and the attainment of a clinical CR after three cycles of chemotherapy were associated with a statistically significant improved EFS. CONCLUSION: Our results indicate that after the delivery of eight cycles of MOPP-ABVD, the addition of low-dose RT does not improve the estimated EFS or OS in pediatric patients with advanced-stage Hodgkin's disease.

Phase II investigational window using carboplatin, iproplatin, ifosfamide, and epirubicin in children with untreated disseminated neuroblastoma: a Pediatric Oncology Group study.

PURPOSE: Children less than 1 year of age with metastatic neuroblastoma NB are at high risk of death. The need to identify new and effective chemotherapy agents is clear. A study was conducted by the Pediatric Oncology Group (POG) to determine the efficacy and safety of administering two courses of a single phase II agent before conventional treatment as a means to evaluate new agents in this setting. PATIENTS AND METHODS: One hundred seventy-three eligible patients more than 1 year of age with disseminated neuroblastoma received two courses of one of the following: ifosfamide (IFOS) 2 g/m2/d for 4 days intravenously (IV) plus mesna; carboplatin (CARB) 560 mg/m2 i.v. over 1 hour; iproplatin (CHIP) 325 mg/m2 IV over 2 hours; or epirubicin (EPIR) 90 mg/m2 i.v. push. Following evaluation for response and toxicity, eligible patients were randomized to receive either cisplatin 90 mg/m2 i.v. on day 1, etoposide 200 mg/m2 i.v. on day 3, cyclophosphamide 150 mg/m2/d orally on days 7 to 13, doxorubicin 35 mg/m2 i.v. on day 14 (CECA), or cisplatin 40 mg/m2 IV on days 1 to 5 and etoposide 200 mg/m2 i.v. on days 2 to 4 alternating at 3-week intervals with cyclophosphamide 150 mg/m2/d orally on days 1 to 7 and doxorubicin 35 mg/m2 IV on day 8 (HDP/VP/CA). An additional 86 patients were randomized to receive either CECA or HDP/VP/CA without initial phase II therapy. RESULTS: After phase II therapy, only 20% of patients experienced grade 3/4 hematopoietic toxicity. No toxic deaths occurred. Objective response rates (partial responses [PRs] plus minor responses [MRs]) following IFOS, CARB, CHIP, and EPIR were 70%, 77%, 67%, and 26%, respectively. Following phase III treatment, there was no statistically significant difference in rates of complete response (CR)/PR or progressive disease (PD), or in time to PD of patients who participated in the phase II window versus those who received only CECA or HDP/VP/CA. CONCLUSION: IFOS, CARB, and CHIP are efficacious in neuroblastoma, are well tolerated, and should be incorporated into primary treatment regimens. Combination regimens using these agents may be possible, since most repeat courses were given within 2 weeks. Administering phase II therapy to untreated patients with high-risk tumors provides a unique and sensitive method to assess new agents without compromising patient outcome.